Blunted proarrhythmic effect of nicorandil in a Langendorff-perfused phase-2 myocardial infarction rabbit model.

Abstract

BACKGROUND:

Nicorandil (a K(ATP) opener) administration is reported to reduce ventricular arrhythmias 4.8 ± 2.2 hours after myocardial infarction (MI). The electrophysiological changes and the effects on dynamic factors and dynamically induced spatially discordant alternans by nicorandil during phase-2 MI are unclear.

METHODS:

Simultaneous voltage and intracellular Ca(2+) (Ca(i)) optical mapping was performed in nine Langendorff-perfused hearts 4-5 hours after coronary artery ligation and nine control hearts. Action potential duration (APD) restitution was constructed and arrhythmogenic alternans was induced by dynamic pacing. Western blot studies (Kir6.1 and Kir6.2) were performed in six more hearts for both groups. Nicorandil (100 μM) was administered after baseline studies.

RESULTS:

Phase-2 MI hearts showed longer APD, slower conduction velocity (CV), and higher ventricular fibrillation (VF) inducibility than the control hearts. Nicorandil shortened and restored APD without significant arrhythmogenic effects, and also increased the rate of Ca(i) reuptake and flattened CV restitution to suppress spatially discordant alternans, which might account for a tendency toward higher VF threshold with nicorandil infusion in phase-2 MI hearts. Immunoblotting studies showed significant down-regulation of K(ATP) protein expression, which was functionally correlated to the blunted APD shortening response to nicorandil.

CONCLUSIONS:

K(ATP) expression is down-regulated in phase-2 MI hearts. Nicorandil restores APD, increases the rate of Ca(i) reuptake, and flattens CV restitution to suppress spatially discordant alternans induction, which ameliorates its proarrhythmic effects during phase-2 MI.

• Authors: Hui-Ling Lee, Po-Cheng Chang, Chung-Chuan Chou, Hung-Ta Wo, Yen Chu, Ming-Shien Wen, San-Jou Yeh, Delon Wu
• Journal: Pacing and clinical electrophysiology : PACE (Pacing Clin Electrophysiol) Vol. 36 Issue 2 Pg. 142-51 (Feb 2013) ISSN: 1540-8159 [Electronic] United States
• PMID: 23121617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.

Chemical References

• Anti-Arrhythmia Agents
• Nicorandil

Topics

• Animals
• Anti-Arrhythmia Agents (therapeutic use)
• Disease Models, Animal
• Humans
• Myocardial Infarction (diagnosis, drug therapy, physiopathology)
• Nicorandil (therapeutic use)
• Perfusion
• Rabbits
• Treatment Outcome
• Ventricular Fibrillation (diagnosis, physiopathology, prevention & control)